The work proposed in this application identifies a novel family of molecules, the Eph receptors (Erythropoietin producing hepatocellular) and their Ephrin ligands, that could be targeted to prevent or reverse the progression of liver fibrogenesis. Despite research progress made in understanding the molecular mechanisms driving the progression of hepatic fibrogenesis, FDA-approved treatments are still severely limited or in some cases restricted to the removal of the etiologic agent. A feature of liver fibrosis is the excessive deposition of extracellular matrix components by activated hepatic stellate cells (HSCs) a process driven by inflammation and recruitment of immune cells at the site of injury. These immune cells provide the pro- inflammatory/fibrogenic microenvironment critical for the transdifferentiation of quiescent HSCs into fibrogenic myofibroblasts. The molecular basis of liver fibrosis is incompletely understood. Ligation of cell?bound Eph receptors to membrane-tethered ephrin ligands initiates a bi-directional signaling cascade affecting diverse biological processes relevant to fibrogenesis including cellular remodelling, angiogenesis, migration/proliferation and epithelial-to-mesenchymal-transition (EMT). The long-term goal of this project is to develop a therapy based on targeting the receptor tyrosine kinase (RTK) EphB2 for the treatment of liver fibrosis/cirrhosis. Using mouse models of liver fibrosis the objective of this exploratory project is to demonstrate that in the liver, EphB2/ ephrin-B signaling is critical for the transdifferentiation of quiescent HSCs into fibrogenic myofibroblasts during fibrogenesis. The central hypothesis being tested in this proposal is that upon chronic liver injury, HSCs upregulate EphB2 and when bound to Ephrin-B ligands expressed on various cells of the liver microenvironment, activated EphB2-expressing HSCs initiate a differentiation process leading to their transformation into fibrogenic myofibroblasts. This hypothesis has been formulated from our preliminary data showing that EphB2 is highly upregulated in both the fibrotic livers of mice and in human liver cirrhosis. HSCs express EphB2 and its deficiency in mice attenuates liver fibrosis in both infectious and non-infectious models. Guided by strong preliminary data the central hypothesis will be tested by pursuing 3 specific aims: Aim 1: Demonstrate that signaling via the cytoplasmic domain of EphB2 is required for liver fibrogenesis. Aim 2: Demonstrate that TGF-?1 regulates EphB2/Ephrin-Bs expression on HSCs. Aim 3: Determine whether therapeutic targeting EphB2 will mitigate liver fibrogenesis. To our knowledge this highly innovative and novel exploratory work is the first to investigate the role of a member of the Eph receptors in non-pathogen driven liver fibrogenesis. The proposed research is significant because it has great translational potential to provide a new therapeutic target (EphB2) for future clinical studies against liver fibrosis/cirrhosis. This project will be the initial focus of my own independent laboratory.